The ultimate goals of this project are to understand the causes and consequences of the expression of the expanded (CAG)n triplet repeat in the Huntington's disease gene and to determine whether this knowledge can be applied to develop an effective mode of therapy for the disorder. It is not clear how expansion of this trinucleotide repeat sequence can lead to the premature death of a specific subset of neurons. Furthermore, the functional characteristics of the protein encoded by the normal IT15 gene must be defined. Man does not constitute a manipulable experimental system in which these issues can be explored and there is presently no genetic animal model of HD. Consequently, we plan to take advantage of the advances which have been made in introducing foreign genes into the mouse to create a collection of transgenic mice that will permit the exploration of three critical issues, the instability of the (CAG)n mutation ,in the mouse, the function of the normal HD allele via the phenotype of a null mutation, and the phenotype produced by the expanded (CAG)n repeat, either in an introduced human gene or appropriately positioned in the endogenous mouse gene. Mice that express human HD constructs and the altered mouse homologue will be bred to establish a genetic animal model of HD which will be subjected to detailed analysis. This project is a challenging undertaking which, like the previous successes in linkage mapping and subsequent cloning of the HD gene, could have a revolutionary impact on all aspects of HD research. If the mouse model expresses significant neuropathology, it would permit a much more detailed analysis of the anatomical and biochemical effects of the expanded (CAG)n IT15 triplet repeat, the genetics of its expression, and its relationship to the excitotoxin hypothesis of neuronal death, while providing an accurate system in which therapeutic approaches could be tested. However, even if mice expressing the HD gene fail to express any abnormality, they will merit continued study to determine the basis for their lack of susceptibility to HD, which might provide a clue to a potential treatment in man.